Non Invasive Free Radical MRI in Stroke

非侵入性自由基 MRI 治疗中风

• 批准号: 8682146
• 负责人: Matthew Scot Rosen
• 金额: $ 25.16万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2016-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8682146
• 关键词: Accounting; Acute; Biological; Biological Markers; Blood - brain barrier anatomy; Brain; Brain Injuries; Cause of Death; Cell Death; Cerebral Infarction; Cerebral Ischemia; Clinical Treatment; Clinical assessments; Contrast Media; Detection; Development; Diagnosis; Diagnostic; Diagnostic Imaging; Electron Spin Resonance Spectroscopy; Electrons; Environment; Extravasation; Free Radicals; Frequencies; Gadolinium DTPA; Generations; Goals; Hemorrhage; Hour; Image; Imaging Techniques; In Vitro; Individual; Infarction; Inflammation; Injection of therapeutic agent; Injury; Intervention; Ischemia; Ischemic Stroke; Kinetics; Life; Link; Magnetic Resonance Imaging; Measures; Mediating; Methodology; Methods; Middle Cerebral Artery Occlusion; Modeling; Monitor; Organism; Oxidative Stress; Patients; Pattern; Performance; Physiologic pulse; Pilot Projects; Process; Production; Radio; Rattus; Reactive Oxygen Species; Recurrence; Relaxation; Reperfusion Injury; Reperfusion Therapy; Resolution; Risk; Rupture; Scientist; Staging; Stroke; Techniques; Technology; Testing; Therapeutic; United States; Work; acute stroke; base; cell injury; clinical application; clinically relevant; disability; excitotoxicity; experience; high risk; imaging modality; improved; in vivo; innovation; insight; interest; novel; prognostic; public health relevance; research clinical testing; small molecule; spatiotemporal; tempol; tool

DESCRIPTION (provided by applicant): Stroke is a leading cause of death and disability. Free radical generation is a well-documented mechanism of ischemia/reperfusion injury, blood brain barrier (BBB) disruption and hemorrhage in ischemic stroke. However, free radicals are difficult to study due to lack of non-invasive tools for in vivo assessment. Conventional MRI is widely used for diagnostic imaging; however, it offers no window into the fundamental processes of oxidative stress following reperfusion injury. There are currently no NMR contrast mechanisms that can detect endogenous production of destructive free radicals. MRI-based biomarkers for visualizing and quantifying the BBB disruption at very early (hyperacute) stages of stroke are similarly unavailable as MRI contrast agents such as Gd-DTPA can only probe ischemic BBB disruption several hours after stroke onset. Free radical sensitive Overhauser-enhanced MRI (OMRI) is a promising technique for imaging the distribution and dynamics of free radicals. We have recently demonstrated a novel, fast and high-resolution OMRI method that offers new perspectives for the free radicals imaging in living organisms. We propose here two complementary aims to implement this novel MRI-based method for non-invasive 3D free radical imaging in ischemic stroke: Aim 1: Detect endogenous free radical production by OMRI as a novel and direct measure of oxidative stress associated with ischemia/reperfusion injury. Aim 2: Detect hyperacute BBB breakdown by making use of a stable free radical probe (TEMPOL) as an exogenously administered contrast agent for OMRI. We will use a rat model of cerebral ischemia/reperfusion to test and refine the ability of our technique to detect endogenous and exogenous free radicals. Both aims have direct clinical relevance. In vivo OMRI of endogenous free radical production will open a non-invasive window into oxidative stress and reperfusion injury, a critical mechanism of cell death in stroke and other forms of brain injury. OMRI will provide an in-depth understanding of spatiotemporal patterns of endogenous free radical production in ischemic brain. Moreover, timely detection of oxidative stress will help tailor interventions to mitigate free radical-induced brain injury in individual patients. Additionally, the use of TEMPOL as a small, exogenous OMRI agent will allow monitoring BBB disruption in stroke at the hyperacute stage, much earlier than the traditional relaxation-based MRI contrast agents that rely on the leakage of larger molecules (such as Gd-DTPA) across the BBB. Altogether, the OMRI technology is a tool that may transform the diagnostic, therapeutic and prognostic approach to acute stroke.

描述（由申请人提供）：中风是死亡和残疾的主要原因。自由基产生是缺血/再灌注损伤，血液脑屏障（BBB）破坏和缺血性中风出血的一种有据可查的机制。但是，由于缺乏用于体内评估的非侵入性工具，自由基很难研究。常规MRI广泛用于诊断成像；但是，它没有提供再灌注损伤后氧化应激的基本过程的窗口。目前没有NMR对比机制可以检测到破坏性自由基的内源性产生。基于MRI的生物标志物可在很早（超急性）阶段可视化和量化BBB的破坏，就像GD-DTPA这样的MRI对比剂（例如GD-DTPA）只能在中风发作后几个小时探测缺血性BBB破坏。自由基敏感的过度大冲突增强MRI（OMRI）是一种成像自由基的分布和动力学的有前途的技术。我们最近展示了一种新颖，快速和高分辨率的OMRI方法，该方法为生物中的自由基成像提供了新的观点。我们在这里提出了两个互补的旨在实施这种基于MRI的新方法，用于缺血性中风中的非侵入性3D自由基成像：AIM 1：检测OMRI的内源性自由基生产，作为与缺血/再灌注损伤相关的新型氧化应激。 AIM 2：通过使用稳定的自由基探针（Tempol）作为OMRI的外源给予对比剂，检测过度急性BBB分解。我们将使用脑缺血/再灌注的大鼠模型来测试和完善我们技术检测内源性和外源性自由基的能力。这两个目标都有直接的临床相关性。内源性自由基生产的体内OMRI将为氧化应激和再灌注损伤打开一个非侵入性窗口，这是中风中细胞死亡的关键机理和其他形式的脑损伤。 OMRI将对缺血性大脑中内源性自由基生产的时空模式有深入的了解。此外，及时检测氧化应激将有助于定制干预措施，以减轻单个患者的自由基引起的脑损伤。此外，将tempol用作小型外源OMRI剂将允许在超急性阶段监测BBB中风中的BBB中断，比依赖于BB较大分子（例如GD-DTPA）泄漏的传统基于弛豫的MRI对比剂要早得多。总体而言，OMRI技术是一种可以将诊断，治疗和预后方法转化为急性中风的工具。